Synthesis and biological evaluation of novel 5‐substituted/unsubstituted triazolothiadiazines as tubulin depolymerizing and vascular disrupting agents with promising antitumor activity.

A novel series of 5‐substituted/unsubstituted [1,2,4]triazolo[3,4‐b][1,3,4] thiadiazine compounds has been achieved successfully through chemoselective reduction of the C = N bond, based on our prior work. Initial biological evaluation illustrated that the most active derivative 7j exhibited significant cell growth inhibitory activity toward MCF‐7, A549, HCT116, and A2780 with the IC50 values of 0.75, 0.94, 2.90, and 4.15 μM, respectively. Most importantly, all the representative analogs did not demonstrate obvious cytotoxic activity against the non‐tumoural cell line HEK‐293 (IC50 > 100 μM). The mechanism study revealed that 7j caused the G2/M phase arrest, induced cell apoptosis in HeLa cells in a concentration‐dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, 7j exerted significant antivascular activity in the wound‐healing and tube formation assays. These observations indicate that 5‐unsubstituted 6,7‐dihydro‐5H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine scaffold might be considered as a potential lead for antitubulin inhibitors to develop highly efficient anticancer agents with potent selectivity over normal human cells. [ABSTRACT FROM AUTHOR]